穿心莲内酯通过抑制 DKK1 的表达使脑胶质瘤对替莫唑胺敏感。

Andrographolide sensitizes glioma to temozolomide by inhibiting DKK1 expression.

机构信息

Department of Pharmacy, The First Afffliated Hospital of Henan University, N. Jinming Ave, Kaifeng, 475004, China.

Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China.

出版信息

Br J Cancer. 2024 Nov;131(8):1387-1398. doi: 10.1038/s41416-024-02842-0. Epub 2024 Sep 12.

DOI:10.1038/s41416-024-02842-0

PMID:39266624

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11473956/

Abstract

BACKGROUND

Temozolomide (TMZ) is the first-line chemotherapeutic drug for gliomas treatment. However, the clinical efficacy of TMZ in glioma patients was very limited. Therefore, it is urgently needed to discover a novel approach to increase the sensitivity of glioma cells to TMZ.

METHODS

Western blot, immunohistochemical staining, and qRT-PCR assays were used to explore the mechanisms underlying TMZ promoting DKK1 expression and andrographolide (AND) inhibiting DKK1 expression. HPLC was used to detect the ability of andrographolide (AND) to penetrate the blood-brain barrier. MTT assay, bioluminescence images, magnetic resonance imaging (MRI) and H&E staining were employed to measure the proliferative activity of glioma cells and the growth of intracranial tumors.

RESULTS

TMZ can promote DKK1 expression in glioma cells and brain tumors of an orthotopic model of glioma. DKK1 could promote glioma cell proliferation and tumor growth in an orthotopic model of glioma. Mechanistically, TMZ increased EGFR expression and subsequently induced the activation of its downstream MEK-ERK and PI3K-Akt pathways, thereby promoting DKK1 expression in glioma cells. Andrographolide inhibited TMZ-induced DKK1 expression through inactivating MEK-ERK and PI3K-Akt pathways. Andrographolide can cross the blood-brain barrier, the combination of TMZ and andrographolide not only improved the anti-tumor effects of TMZ but also showed a survival benefit in an orthotopic model of glioma.

CONCLUSION

Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression.

摘要

背景

替莫唑胺（TMZ）是治疗神经胶质瘤的一线化疗药物。然而，TMZ 在神经胶质瘤患者中的临床疗效非常有限。因此，迫切需要发现一种新的方法来提高神经胶质瘤细胞对 TMZ 的敏感性。

方法

使用 Western blot、免疫组织化学染色和 qRT-PCR 检测 TMZ 促进 DKK1 表达和穿心莲内酯（AND）抑制 DKK1 表达的机制。HPLC 用于检测穿心莲内酯（AND）穿透血脑屏障的能力。MTT 测定、生物发光图像、磁共振成像（MRI）和 H&E 染色用于测量神经胶质瘤细胞的增殖活性和颅内肿瘤的生长。

结果

TMZ 可促进神经胶质瘤细胞和神经胶质瘤原位模型中的脑肿瘤中 DKK1 的表达。DKK1 可促进神经胶质瘤原位模型中的神经胶质瘤细胞增殖和肿瘤生长。在机制上，TMZ 增加了 EGFR 的表达，随后诱导其下游 MEK-ERK 和 PI3K-Akt 通路的激活，从而促进神经胶质瘤细胞中 DKK1 的表达。穿心莲内酯通过使 MEK-ERK 和 PI3K-Akt 通路失活来抑制 TMZ 诱导的 DKK1 表达。穿心莲内酯可以穿透血脑屏障，TMZ 和穿心莲内酯的联合不仅提高了 TMZ 的抗肿瘤作用，而且在神经胶质瘤的原位模型中也显示出了生存获益。